Niemann-Pick disease is the name given to a class of inherited lipid storage diseases. Four types of the disease are recognized, Types A, B, C and D. Niemann-Pick disease type C (NP-C) is an autosomal recessive neurovisceral lipid storage disorder which leads to systemic and neurological abnormalities (Brady et al., 1989). Clinical features of the disease include variable hepatosplenomegaly, vertical supra-nuclear ophthalmoplegia, progressive ataxia, dystonia and dementia (Pentchev et al., 1989). Cataplexy and seizures may occur later in the course of the illness. NP-C is characterized by phenotypic variability, with onset ranging from birth to early adulthood (Fink et al., 1989). Type C Niemann-Pick disease differs from types A and B in that the latter two forms are lipidoses resulting from a lesion in the sphingomyelinase gene located on chromosome 11 (Pereira et al, 1991). In contrast, the underlying genetic defect of NP-C remains unknown. Type D Niemann-Pick disease (also known as the Nova Scotia variant) is allelic to type C and occurs in descendents of western Nova Scotians.
The biochemical hallmark of NP-C cells is the abnormal accumulation of unesterified cholesterol in lysosomes, which results in delayed homeostatic regulation of both uptake and esterification of low density lipoprotein (LDL) cholesterol (Sokol et al., 1988; Blanchette-Mackie et al., 1988; Pentchev et al, 1994; Pentchev et al., 1987). Accumulation of lysosomal cholesterol in the cells of NP-C sufferers can be detected cytochemically by the cholesterol-specific fluorescent dye, filipin. Normally, endocytosed LDL-derived cholesterol is mobilized from lysosomes to the endoplasmic reticulum for esterification. As a result, there is little free cholesterol accumulation in lysosomes detectable by filipin staining in normal cells. In contrast, in NP-C cells the lysosomal accumulation of the endocytosed LDL-derived free cholesterol results in a specific perinuclear filipin-staining pattern. Biochemically, the NP-C phenotype can most conviently be monitored by LDL-induced cholesterol ester synthesis. Cholesterol ester synthesis is markedly stimulated by LDL in normal cells, but not in NP-C cells.
Two independent murine models having autosomal recessive lysosomal storage defects have been described (Morris et al., 1982; Miyawaki et al., 1982, Sakiyama et al, 1982). The pathological features of these murine mutants are similar to human NP-C (Higashi et al., 1991; Ohno et al., 1992), but, to date, the genetic defect in these mouse lines remains uncharacterized.
If the gene underlying NP-C could be isolated, it could facilitate the detection, diagnosis, and perhaps treatment of the disease. It is the objective of this invention to provide a human cDNA corresponding to the gene for NP-C, as well as the cDNA underlying the NP-C murine models.